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— Research

What’s old may be NEW AGAIN

Repurposing drugs for COVID-19

A molecule known as ACE2 sits like a doorknob on the outer surfaces of cells that line the lungs’ passageways. Since early 2020, researchers have known that SARS-CoV-2 primarily uses the ACE2 doorknob to enter these cells and establish a COVID-19 respiratory infection. Finding a way to lock out that interaction as a means to treat infection has become the goal of many research studies.

To speed up the search, many researchers have turned to testing repurposed drugs — medicines already known to be safe for human use because they are FDA-approved for other conditions.

Before it became infamous for its role in COVID-19 infections, ACE2 was known to regulate blood pressure. And since prescription statins — widely used cholesterol-lowering drugs — can affect ACE2, UC San Diego Health researchers analyzed the electronic medical records of 170 statin-taking patients with COVID-19 to see what effect the medications had on virus vulnerability.

They found that statin use prior to hospital admission for COVID-19 was associated with a more than 50 percent reduction in risk of developing severe COVID-19, compared to those with COVID-19 but who were not taking statins. Patients with COVID-19 who were taking statins prior to hospitalization also recovered faster. The study, led by Lori Daniels, MD, professor and director of the Cardiovascular Intensive Care Unit at UC San Diego Health, and Karen Messer, PhD, professor and chief of the Division of Biostatics and Bioinformatics, was published in the American Journal of Cardiology.

Another UC San Diego School of Medicine team discovered that SARS-CoV-2 can’t grab onto ACE2 without a carbohydrate called heparan sulfate, also found on lung cell surfaces, where it acts as a co-receptor for viral entry. “ACE2 is only part of the story,” said Jeffrey Esko, PhD, Distinguished Professor of Cellular and Molecular Medicine at UC San Diego School of Medicine and co-director of the Glycobiology Research and Training Center. “It isn’t the whole picture.”

“It isn’t the whole picture.”

— Jeffrey Esko, PhD

Esko’s team discovered that heparin — an FDA-approved form of heparan sulfate widely used to prevent and treat blood clots — reduces the ability of SARS-CoV-2 to infect human cells cultured in the lab by up to 90 percent. Essentially, the heparin acts as bait to lure and bind the coronavirus, keeping it away from human cells. The study was published in Cell.

Elsewhere, UC San Diego physician-scientists like Constance Benson, MD, professor of medicine, and Dan Sweeney, MD, helped conduct clinical trials of remdesivir, an antiviral originally designed to treat Ebola and Marburg infections, and the first repurposed drug approved by the FDA for treating COVID-19. It was found to shorten hospital stays and recovery time.

Not every repurposed drug is a success story. Atul Malhotra, MD, research chief of pulmonary, critical care and sleep medicine at UC San Diego Health, led a Phase III clinical trial investigating whether tocilizumab, a monoclonal antibody treatment for arthritis and other inflammatory diseases, might significantly improve the outcomes of patients with severe COVID-19 pneumonia.

It did not, Malhotra and colleagues reported in The New England Journal of Medicine, though they did observe a modest decrease in length of hospital stays and days on mechanical ventilators. Even when repurposed drugs do not achieve hoped-for results, Malhotra said, lessons are learned, which can guide new studies and help focus attention where it is most effective.